DESCRIPTION: (Applicant's Abstract) This proposal is directed at continuing a long standing research project concerning the development and use of in vivo voltammetry for the detections of the neurotransmitter dopamine. In prior research supported by the National Science Foundation the use of fast-scan cyclic voltammetry with carbon-fiber microelectrodes was shown to be a sensitive and selective approach to the detection of dopamine neurotransmission in brain tissue. Release evoked by impulse flow and subsequent uptake by the neuronal transporter system was kinetically characterized in select regions of the brain of anesthetized rats. In addition, modification of these processes by pharmacological intervention was explored. In this application we propose to use this technique to investigate topics directly related to the subject of drug abuse. This new research direction is made possible by two new developments. First, in the last six months we have developed a protocol that allows for voltammetric measurements in freely moving rats. The method developed retains the high spatial and temporal resolution that is the unique attribute of this approach. This method allows dopamine neurotransmission to be observed in real time in a behaving animal. Second, through a collaboration with Marc Caron, Duke University, we have begun an investigation of mice that have a genetic deletion of the dopamine transporter. This knock out of a central site of action of two drugs of abuse, amphetamine and cocaine, enables new insights into their mode of action. In the proposed research these new developments will be used to investigate the brain reward system often associated with drugs of abuse, and to directly investigate the actions of cocaine and amphetamine. Specifically, the investigation of the brain reward system will focus on the role of dopamine in the classic intracranial self-stimulation experiment. The experiments with the animals with knock-outs of the dopamine transporter will examine the effect of this genetic alteration in the intact animal.